The immunoregulatory function of lymphocytes from patients with Crohn's disease was studied. Previous work indicated that peripheral blood lymphocytes from many patients with mild or inactive disease have excessive suppression of pokeweed mitogen stimulated immunoglobulin synthesis in vitro. Current studies showed that the proportion of peripheral blood lymphocyte subclasses, as defined by monoclonal antibodies Leu 2 (and OKT 8), and Leu 4 were normal, and the Leu 3/Leu 2 ratios were normal. However, the percentage of a subpopulation of lymphocytes defined by reactivity with both Leu 2 and HNK-1 (Leu 7) was found to be increased; elimination of cells reactive with OKT 8 or HNK-1 removed the excessive suppressor activity. Furthermore, the percentage of Leu2+, HNK-1+ lymphocytes correlated significantly with the suppressor function in pokeweed mitogen stimulated cultures. Thus, the excessive suppressor activity of peripheral blood lymphocytes in Crohn's disease is due to the activity of a newly defined subpopulation of cells having the Leu 2+, HNK-1+ phenotype. To further define the role of immunoregulatory cells in Crohn's disease, we have studied lymphocytes isolated from the lamina propria of gut specimens obtained from Crohn's patients undergoing surgical resection. We have found that although the Leu 3/Leu 2 ratios are diminished compared to peripheral blood, lymphocytes from the lamina propria do not manifest excessive suppressor function, but, in fact, augment immunoglobulin synthesis. Only a small percentage of lamina propria lymphocytes from Crohn's patients have the Leu 2+, HNK-1+ phenotype which was found to be increased in peripheral blood of patients with Crohn's disease, and which correlates with excessive suppressor function. Studies are in progress to investigate the mechanism of activation and function of subpopulations of lymphocytes isolated from the lamina propria. Further understanding of the immunoregulatory function of lymphocytes in the lamina propria of patients with inflammatory bowel disease may be important in understanding the inflammatory lesions in the bowel of Crohn's patients.